French researchers have initiated a pivotal clinical trial investigating a novel treatment approach for pseudoxanthoma elasticum (PXE), a rare inherited disorder affecting approximately 1 in 25,000-50,000 people. The Phase II PROPHECI trial aims to determine if oral pyrophosphate (PPi) supplementation can effectively combat the abnormal calcification that characterizes the disease.
PXE results from mutations in the ABCC6 gene, leading to chronic deficiency of pyrophosphate - a natural anti-calcification factor in blood. The condition primarily affects the retina, skin, blood vessels, and kidneys, often causing serious complications including central vision loss, peripheral arterial disease, and increased risk of stroke.
"Until recently, only symptomatic treatments were available for PXE patients," explains Professor Georges Lefthériotis, Principal Investigator at the University Hospital of Nice. "This trial represents the first systematic evaluation of PPi supplementation as a potential disease-modifying therapy."
The double-blind, placebo-controlled study will enroll 99 patients across two French PXE expert centers in Nice and Angers. Participants will be randomized in a 2:1 ratio to receive either daily oral PPi capsules (40 mg/kg) or matching placebo for 12 months.
Novel Trial Design and Endpoints
The trial employs sophisticated imaging techniques to measure treatment efficacy. The primary endpoint focuses on changes in arterial calcification scores measured by CT scanning. Secondary outcomes include effects on:
- Peripheral arterial disease progression
- Ophthalmologic complications
- Skin lesions
- Quality of life measures
"We've incorporated multiple assessment methods to capture the complex nature of PXE," notes Professor Ludovic Martin, co-Principal Investigator at the University Hospital of Angers. "This comprehensive approach will help us better understand both the clinical impact and patient experience."
Safety and Monitoring
The research team has carefully considered safety aspects, particularly regarding PPi's effects on phosphate metabolism. Strict monitoring protocols are in place, with regular assessment of blood chemistry and potential adverse events. Patients with impaired renal function or certain metabolic disorders are excluded from participation.
The trial's design addresses several challenges inherent to rare disease research, including appropriate sample size calculations and reliable biomarker selection. Results are expected by 2026 and could potentially establish PPi supplementation as the first targeted therapy for PXE.
Future Implications
Beyond evaluating PPi's therapeutic potential, the PROPHECI trial aims to validate new biomarkers and endpoints for future PXE research. This could prove invaluable for subsequent clinical trials in this rare disease space.
"If successful, this trial could represent a significant advancement in PXE treatment," concludes Professor Lefthériotis. "More importantly, it may provide a template for future rare disease trials where measuring clinical benefit presents unique challenges."
